New vaccine may protect against coronavirus variants, similar viruses

• Researchers have recently developed a novel vaccine candidate named mosaic-8 that could protect against both SARS-CoV-2 variants and other closely related coronaviruses that could cause outbreaks in the future.
• The researchers found that mice and non-human primate models immunized with mosaic-8 produced a broadly neutralizing antibody response against SARS-CoV-2 variants and related coronaviruses.
• The mosaic-8 vaccine also conferred protection against severe disease due to SARS-CoV-2 variants and SARS-CoV-1 in these animal models.
• This new vaccine could eliminate the need for updating the vaccine with the emergence of new SARS-CoV-2 variants or a disease outbreak due to a closely related coronavirus.

A recent study published in the journal Science shows that mosaic-8, a nanoparticle-based vaccine candidate, could confer broad protection against SARS-CoV-2 variants of concern and other related coronaviruses.

The study’s co-author Dr. Pamela J. Bjorkman, a professor at the California Institute of Technology, said, “SARS-CoV-2 has proven itself capable of making many new variants that have prolonged the global COVID-19 pandemic. In addition, the fact that three betacoronaviruses—SARS-CoV, MERS-CoV, and SARS-CoV-2—have spilled over into humans from animal hosts in the last 20 years illustrates the need for making broadly protective vaccines.”

Dr. Bjorkman added that it’s not possible to predict which virus or viruses among the vast numbers found in animals will evolve in the future to infect humans and cause another epidemic or pandemic.

“What we’re trying to do is make an all-in-one vaccine protective against SARS-like betacoronaviruses regardless of which animal viruses might evolve to allow human infection and spread. This sort of vaccine would also protect against current and future SARS-CoV-2 variants without the need for updating,” Dr. Bjorkman said.

Need for a universal vaccine

The emergence of new SARS-CoV-2 variants has prolonged the COVID-19 pandemic. COVID-19 vaccines approved so far were developed to target the wild-type SARS-CoV-2 spike protein.

A large number of mutations in the spike protein of the Omicron variant has diminished the ability of the existing COVID-19 vaccines to prevent breakthrough infections. Thus, COVID-19 vaccines are currently being updated to increase their effectiveness against potential new variants of concern.

SARS-CoV-2 belongs to the genus sarbecovirus, which also includes other similar viruses. For instance, SARS-CoV-1, the virus responsible for the severe acute respiratory syndrome (SARS) outbreak in 2003, is also a member of the sarbecovirus.

Moreover, a number of sarbecoviruses have been found in bats, with some capable of binding to the same receptor on human cells as SARS-CoV-2 and SARS-CoV-1. Thus, there is a possibility of another sarbecovirus jumping from an animal species to humans and causing a new epidemic or pandemic.

This underscores the need for a vaccine that could confer protection against newer SARS-CoV-2 variants and other sarbecoviruses.

Targeting conserved regions

The spike protein expressed on the surface of SARS-CoV-2 plays an important role in mediating the entry of the virus into human cells. Specifically, the receptor-binding domain (RBD) of the spike protein interacts with the angiotensin-converting enzyme 2 (ACE2) receptors expressed by almost all human tissues, facilitating the entry of the virus into human cells.

Immunization with a COVID-19 vaccine generates an immune response against the RBD of the wild-type SARS-CoV-2 spike protein. This immune response includes neutralizing antibodies that bind to the RBD and prevent the spike protein from interacting with ACE2 receptors, thus inhibiting the infection of human cells.

These neutralizing antibodies predominantly bind to two subregions of the RBD. However, these subregions of the spike protein RBD are prone to mutations, with their sequences showing considerable variation among SARS-CoV-2 variants.

This explains the waning neutralizing antibody response against SARS-CoV-2 variants after vaccination. Furthermore, these subregions of the spike protein RBD show a high degree of sequence variability among different sarbecoviruses.

The authors of the present study had previously discovered two other subregions of RBD that are conserved among these sarbecoviruses. Moreover, fewer mutations are observed in these subregions in SARS-CoV-2 variants of concern.

Researchers have now developed a vaccine that elicits an immune response against these conserved subregions of the spike protein RBD. This vaccine, called mosaic-8, includes a spike protein RBD from the SARS-CoV-2 and seven other related sarbecoviruses that are chemically attached to a protein nanoparticle.

The presence of RBDs from eight different sarbecoviruses teaches the immune system to elicit a response against a broad range of proteins. The use of protein fragments that are more likely to be conserved across sarbecoviruses suggests that this vaccine could also identify sarbecovirus RBDs that were not present on the nanoparticle.

In other words, the mosaic-8 vaccine could produce a cross-reactive antibody response against a broad range of sarbecoviruses. Such a vaccine could potentially eliminate the need to update the vaccine with the emergence of new variants or sarbecoviruses that jump from animals to cause disease in humans.

Neutralizing antibody response

In the present study, the researchers assessed the ability of the mosaic-8 vaccine to elicit an immune response in a mouse model and rhesus macaques.

Since mice are relatively resistant to a SARS-CoV-2 infection, the researchers used genetically modified mice that express the human ACE2 receptor to make them susceptible to a SARS-CoV-2 infection.

These mice were immunized with the mosaic-8 vaccine or homotypic SARS-CoV-2 RBD nanoparticles, which were conjugated with only the RBD from SARS-CoV-2 instead of 8 different RBD fragments.

Immunization with the mosaic-8 vaccine resulted in lower serum levels of neutralizing antibodies against the SARS-CoV-2 variants than homotypic SARS-CoV-2 RBD nanoparticles. Notably, vaccination with the mosaic-8 vaccine resulted in higher neutralizing antibody titers against SARS-CoV-1 and other sarbecovirus spike proteins. Similarly, rhesus macaques immunized with mosaic-8 also showed a strong neutralizing antibody response against SARS-CoV-2 variants of concern and other sarbecoviruses.

Although RBDs from sarbecoviruses such as SARS-CoV-1 were not included in the mosaic-8 vaccine, immunization with this nanoparticle vaccine resulted in a strong neutralizing antibody response against these viruses. In other words, the use of the conserved RBD subregions on the mosaic-8 vaccine potentially resulted in cross-reactivity against a range of sarbecoviruses.

Protection against virus challenge

To compare the ability of this nanoparticle-based vaccine to protect against severe disease, mice previously immunized with the mosaic-8 vaccine, the homotypic SARS-CoV-2 RBD nanoparticles, or unconjugated nanoparticles were infected with either SARS-CoV-2 or SARS-CoV-1.

Mice infected with SARS-CoV-2 tend to show weight loss following the onset of infection. Consistent with this, infection with either virus resulted in significant weight loss and death in the control group injected with unconjugated nanoparticles.

The mice immunized with mosaic-8 nanoparticles did not show weight loss after a SARS-CoV-1 or SARS-CoV-2 infection. The mosaic-8 vaccine also suppressed viral replication in the lungs and the upper respiratory tract and protected the mice from death after infection with either virus.

Similar experiments in rhesus macaques showed that immunization with the mosaic-8 vaccine was protective against both the SARS-CoV-2 Delta variant and SARS-CoV-1. In other words, the mosaic-8 vaccine conferred protection against both SARS-CoV-1 and SARS-CoV-2 variants of concern.

The homotypic SARS-CoV-2 RBD nanoparticles exerted protective effects against a SARS-CoV-2 infection in mice, but not a SARS-CoV-1 infection. This further demonstrates the use of RBDs from 8 different sarbecoviruses protected against not only SARS-CoV-2 variants but also against other related viruses not represented on mosaic-8 nanoparticles.

The researchers will be conducting Phase 1 clinical trials to examine if these results obtained with mosaic-8 in animal models can be replicated in humans.

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